tbuckley/cabot-search huggingface dataset:
Abstract 2887: Three dimensional colon cancer organoids model the response to CEA CD3 T cell engagers
Authors: Alvaro Teijeira, Itziar Migueliz, Saray Garasa, Marina Bacac, Christian Klein, Ignacio Melero
Journal: Cancer Research (2022)

Abstract Rationale: The CEA-CD3 T cell bispecific antibody cibisatamab (CEA-TCB) is currently undergoing clinical trials. Here we study its performance against three-dimensional tumor organoids in cocultures with T cells as compared to a higher affinity CEACAM5-CD3 (CEACAM5-TCB) bispecific antibody using time-lapse confocal microscopy. Methods: Pre-labelled spheroids derived from colon cancer cell lines and primary organoids derived from four colorectal cancer surgical specimens, which expressed different graded levels of CEA, were exposed in cocultures to T lymphocytes. Cocultures were treated with CEA-CD3 T-cell engagers and were followed by live confocal microscopy. Caspase 3 activation detected in real-time was used as an indicator of tumor cell death. Co-cultures were also set up with autologous tumor-associated fibroblasts to test the co-stimulatory effect of a fibroblast activated protein (FAP)- targeted 4-1BBL bispecific antibody fusion protein currently undergoing clinical trials. Results: Tumor-cell killing of 3D colon carcinoma cultures was dependent on the levels of surface CEA expression, in such a way that the lower affinity agent (CEA-TCB) did not mediate killing by human preactivated T cells below a certain CEA expression threshold, while the high affinity construct (CEACAM5-TCB) remained active on the low CEA expressing organoids. Modelling heterogeneity in the levels of CEA expression by coculturing CEA high and low organoids showed measurable but weak bystander killing. Cocultures of tumor organoids, autologous fibroblasts and T cells allowed to observe a costimulatory effect of anti-FAP-4-1BBL both to release IFNγ and to attain more efficacious tumor cell killing. Conclusion: Three-dimensional tumor cocultures with T cells using live confocal microscopy provide suitable models to test the requirements for colon-cancer redirected killing as elicited by CEA-targeted T-cell engagers undergoing clinical trials and treatment allow combinations to be tested in a relevant preclinical system. Citation Format: Alvaro Teijeira, Itziar Migueliz, Saray Garasa, Marina Bacac, Christian Klein, Ignacio Melero. Three dimensional colon cancer organoids model the response to CEA CD3 T cell engagers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2887.
Abstract 5006: Computational analysis of hypoxia-inducible factor 1-alpha and UBS109 in hepatocellular carcinoma
Authors: Neha Bahadur Merchant, Santosh Kumar Behera, Afroz Alam, Ganji Purnachandra Nagaraju, Riyaz Basha
Journal: Cancer Research (2022)

Abstract Hypoxia-inducible factor 1-alpha (HIF-1α) is a heterodimeric transcription factor, which is elevated during hypoxic conditions in several malignancies. HIF-1α is known to stimulate hypoxia-responsive genes that are linked with malignant properties viz.: progression, metastasis, and resistance to therapy. The objective of the present study is to target HIF-1α by potential phytodrug, curcumin and its monocarbonyl analog UBS109 in hepatocellular carcinoma (HCC). Curcumin has been known to exhibit therapeutic properties for the management of HCC due to its powerful anti-inflammatory and antioxidant properties as well as its ability to regulate multiple signaling pathways. UBS109 possesses comparable antitumor and anti-inflammatory properties as curcumin without any of its limitations. To analyze the binding capacity and ligand efficacy of HIF-1α against curcumin and UBS109, computational approaches were applied including molecular docking and dynamics simulation that can provide detailed understanding of its implication in HCC treatment and a deeper analysis of the protein-drug interaction. Citation Format: Neha Bahadur Merchant, Santosh Kumar Behera, Afroz Alam, Ganji Purnachandra Nagaraju, Riyaz Basha. Computational analysis of hypoxia-inducible factor 1-alpha and UBS109 in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5006.
Abstract 1622: Signaling of cyclin-dependent kinase 12 (CDK12) in prostate cancer cell lines
Authors: Victor Chalfant, Carlos Riveros, Sanjeev Shukla, Teruko Osumi, K Balaji
Journal: Cancer Research (2022)

Abstract Cyclin-dependent kinase 12 (CDK12) belongs to the cyclin-dependent kinase (CDK) family of serine/threonine protein kinases. In contrast to CDKs which promote cell cycle progression, CDK12 is a transcriptional regulator of various cellular functions, most importantly cellular response to DNA damage and stress. Genomic alterations in CDK12 have been detected in up to 7% of patients with metastatic castration-resistant prostate cancer (CRPC). Phosphoproteomic studies have revealed that Protein Kinase D1 (PrKD1), another member of the serine/threonine kinase family, is the only kinase known to phosphorylate CDK12 at serine 681 (s681) and serine 685 (s685). While there is an increasing body of literature on CDK12 downstream signaling, there is almost no published data on upstream effectors or regulation of CDK12. Using site-directed mutagenesis, we generated CDK12 s681a and s681a+s685 mutants and transfected them into stable C4-2 and C4-2-PrKD1 cell lines to evaluate the interaction between CDK12 and PrKD1. Immunoprecipitation and immunoblotting revealed that endogenous CDK12 is stable in C4-2 cells with known levels of PrKD1 expression. However, stable transfection of C4-2-PrKD1 cells with wild-type CDK12 resulted in the degradation of nascent CDK12, whereas the non-phosphorylated mutants (s681 and s681+s685) remained stable. Our results suggest that PrKD1-mediated phosphorylation of s681and/or s685 residues affect CDK12 stability in C4-2-PrKD1 cells. We confirmed this finding by treating C4-2-PrKD1 cells with MG-132, a 26 S proteasome inhibitor, and repeating the experiment. Proteasomal inhibition rescued nascent transfected CDK12 levels even after PrKD1 phosphorylation. Our study demonstrates that CDK12 degradation might be mediated by PrKD1 phosphorylation at s681 and/or s685. Because PrKD1 and CKD12 are dysregulated across cancers, the results herein presented have potential implications for the treatment of not only prostate cancer but also other human malignancies. Citation Format: Victor Chalfant, Carlos Riveros, Sanjeev Shukla, Teruko Osumi, K Balaji. Signaling of cyclin-dependent kinase 12 (CDK12) in prostate cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1622.
Abstract 4134: Stromal FAP expression is associated with MRI visibility and patient survival in prostate cancer
Authors: Teijo Pellinen, Kevin Smith, Sami Blom, Riku Turkki, Annabrita Hemmes, Katja Välimäki, Juho Eineluoto, Anu Kenttämies, Stig Nordling, Olli Kallioniemi, Antti Rannikko, Tuomas Mirtti
Journal: Cancer Research (2022)

Abstract Some clinically significant prostate cancers (PCa) are missed by magnetic resonance imaging (MRI). We asked if the tumor stroma in surgically treated primary PCa lesions positive or negative with MRI are different in their cellular and molecular properties, and whether the differences are reflected to the clinical course of the disease. We profiled the stromal and immune cell composition of MRI-classified tumor lesions by applying multiplexed fluorescence immunohistochemistry (mfIHC) and automated image analysis in a clinical cohort of 343 patients (Cohort I). We compared stromal variables between MRI-visible, invisible lesions, and benign tissue and assessed the predictive significance for biochemical recurrence (BCR) and disease-specific survival (DSS) using Cox regression and Log rank analysis. Subsequently, we carried out a prognostic validation of the identified biomarkers in a population-based cohort of 319 patients (Cohort II). MRI true-positive lesions are different from benign tissue and MRI false-negative lesions in their stromal composition. CD163-positive cells and fibroblast activation protein (FAP)-positive cells were more abundant in MRI true-positive than in MRI false-negative lesions or benign areas. In MRI true-visible lesions, a high proportion of stromal FAP-positive cells was associated with PTEN status and increased immune infiltration (CD8+, CD163+), and predicted elevated risk for BCR. High FAP phenotype was confirmed to be a strong indicator of poor prognosis in two independent patient cohorts using also conventional IHC. The molecular composition of the tumor stroma may determine whether early prostate lesions are detectable by MRI and associates with survival after surgical treatment. Citation Format: Teijo Pellinen, Kevin Smith, Sami Blom, Riku Turkki, Annabrita Hemmes, Katja Välimäki, Juho Eineluoto, Anu Kenttämies, Stig Nordling, Olli Kallioniemi, Antti Rannikko, Tuomas Mirtti. Stromal FAP expression is associated with MRI visibility and patient survival in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4134.
Safety and efficacy of eptinezumab for migraine prevention in patients with two-to-four previous preventive treatment failures (DELIVER): a multi-arm, randomised, double-blind, placebo-controlled, phase 3b trial
Authors: Messoud Ashina, Michel Lanteri-Minet, Patricia Pozo-Rosich, Anders Ettrup, Cecilie Laurberg Christoffersen, Mette Krog Josiassen, Ravinder Phul, Bjørn Sperling
Journal: The Lancet Neurology (2022)
Abstract 3895: Moxidectin unravels the role of Hippo-YAP pathway in maintaining immunity of pediatric glioblastoma
Authors: Itishree Kaushik, Shreyas Gaikwad, Sanjay K. Srivastava
Journal: Cancer Research (2022)

Abstract Pediatric glioblastoma multiforme (GBM) is considered to be the second most lethal childhood cancer type after leukemia. Recent preclinical, clinical and genomic studies have highlighted upon the role of Hippo-Yap pathway in the progression of pediatric GBM. In addition, recent studies have established the role of YAP in creating immune suppressive tumor microenvironment (TME) facilitating drug resistance, recurrence and metastasis of GBM tumors. Herein, we report that ‘moxidectin’ an anti-helminthic drug inhibits the proliferation of SF268, SF295, SF188 and CT-2A Luc GBM cells by inducing apoptosis. Immunoblotting and immunofluorescence microscopy studies show that moxidectin mediates its effects by inhibiting MEK-ERK pathway, a regulator of Hippo-YAP signaling. As a result, moxidectin suppressed the nuclear translocation and transcriptional activity of YAP/TAZ-TEAD complex. Oral administration of 3.5mg/kg moxidectin suppressed the growth of GBM tumors by 90% in intracranial tumor model. Ex-vivo analysis of excised tumors confirmed the observations made in in vitro studies. We further conducted immunophenotyping on the excised tumors from both control and moxidectin treated mice to evaluate the effect of moxidectin on immune cell markers in TME and Tumor Draining Lymph Nodes (TDLNs). Our analysis indicated that treatment with moxidectin suppressed the immune suppressive TME created by GBM tumor. Interestingly, moxidectin enhanced antigen presentation in the TDLN. Indicating that it might play a role in activating the peripheral immune response. Moxidectin is an FDA approved drug and any findings from our research will promote its further investigation as a potential therapeutic agent for GBM patients. Citation Format: Itishree Kaushik, Shreyas Gaikwad, Sanjay K. Srivastava. Moxidectin unravels the role of Hippo-YAP pathway in maintaining immunity of pediatric glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3895.
Abstract 6118: Tumor-derived GDF-15 promotes immune escape of tumors by functional alteration of the myeloid compartment
Authors: Markus Haake, Beatrice Haack, Sabrina Genßler, Julia Weigandt, Marlene Auer, Vincent Thiemann, Wahid M. Haq, Melanie Haag, Florian Wedekink, Birgitt Fischer, Kathrin Klar, Matthias Wölfl, Christine Schuberth-Wagner, Jorg Wischhusen
Journal: Cancer Research (2022)

Abstract Background: Growth and differentiation factor 15 (GDF-15), a divergent member of the TGF-β protein superfamily, shows low physiological baseline expression. GDF-15 is, however, strongly upregulated during pregnancy. It is further induced in stressed and damaged tissues, where it limits immune infiltration and inflammation. In solid tumors, GDF-15 was shown to be a key inhibitor of T-cell infiltration. While this might already explain the strong correlation between GDF-15 overexpression and poor survival with or without checkpoint-based immunotherapy, effects of GDF-15 on dendritic cells and monocytes may further shape the tumor microenvironment. Methods: To analyze the impact of GDF-15 in murine tumor models, GDF-15 was either deleted by CRISPR/CAS9 gene editing or neutralized by administration of a blocking antibody. Effects on tumor growth were recorded and the composition of the tumor microenvironment was characterized by flow cytometry. More detailed insight into tumor-immune interactions was obtained via the CrownBio Mouse I/O RNA-Seq Panel. Specific effects on polarization of innate and on antigen-specific priming of adaptive immune cells were confirmed in cellular assays in vitro. Results: Tumor-derived GDF-15 modulates the tumor microenvironment by inhibiting infiltration and activation of myeloid cells. GDF-15 thereby impairs the induction of antitumoral immune responses. Deletion of GDF-15 enhances infiltration of innate cells into immune-excluded tumors, supports the priming of naïve T cells by dendritic cells and generates a pro-inflammatory tumor microenvironment. In vitro, GDF-15 inhibits DC maturation and synapse formation, thus preventing successful T-cell activation. Moreover, GDF-15 interferes with M1 polarization of macrophages. Conclusion: GDF-15 secretion helps tumors to generate a microenvironment that is poorly infiltrated by immune cells. GDF-15 further polarizes myeloid cells towards a tumor-promoting, anti-inflammatory phenotype. By inducing a more pro-inflammatory tumor phenotype, anti-GDF-15 antibodies may synergize with other immunotherapeutic agents. A clinical trial combining anti-GDF-15 (CTL002) with anti-PD-1 (NCT04725474) is ongoing. Citation Format: Markus Haake, Beatrice Haack, Sabrina Genßler, Julia Weigandt, Marlene Auer, Vincent Thiemann, Wahid M. Haq, Melanie Haag, Florian Wedekink, Birgitt Fischer, Kathrin Klar, Matthias Wölfl, Christine Schuberth-Wagner, Jorg Wischhusen. Tumor-derived GDF-15 promotes immune escape of tumors by functional alteration of the myeloid compartment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6118.
Allosteric Modulators of Metabotropic Glutamate Receptors as Novel Therapeutics for Neuropsychiatric Disease
Authors: Deborah J. Luessen, P. Jeffrey Conn
Journal: Pharmacological Reviews (2022)

Metabotropic glutamate (mGlu) receptors, a family of G-protein-coupled receptors, have been identified as novel therapeutic targets based on extensive research supporting their diverse contributions to cell signaling and physiology throughout the nervous system and important roles in regulating complex behaviors, such as cognition, reward, and movement. Thus, targeting mGlu receptors may be a promising strategy for the treatment of several brain disorders. Ongoing advances in the discovery of subtype-selective allosteric modulators for mGlu receptors has provided an unprecedented opportunity for highly specific modulation of signaling by individual mGlu receptor subtypes in the brain by targeting sites distinct from orthosteric or endogenous ligand binding sites on mGlu receptors. These pharmacological agents provide the unparalleled opportunity to selectively regulate neuronal excitability, synaptic transmission, and subsequent behavioral output pertinent to many brain disorders. Here, we review preclinical and clinical evidence supporting the utility of mGlu receptor allosteric modulators as novel therapeutic approaches to treat neuropsychiatric diseases, such as schizophrenia, substance use disorders, and stress-related disorders.
Abstract 2934: Pattern of PIK3CA co-alterations in endometrial cancer
Authors: Madhuri Paul, Frank J. Scarpa, Rachel Daringer, Sally Agersborg, Vincent Anthony Funari, Forrest Blocker
Journal: Cancer Research (2022)

Abstract Purpose: Aberrant PI3K pathway activation drives tumor proliferation and survival. The aim of this study was to identify PI3K pathway activation patterns in endometrial cancer by profiling mutational prevalence and co-mutation with PTEN and TP53. Methods: Molecular profiles of 1,180 unique cancer (endometrial, breast, lung, and colorectal) patients’ formalin-fixed paraffin-embedded tissue samples were analyzed. Samples were evaluated using a 323 gene NGS panel utilizing the QIAseq targeted DNA chemistry. Fisher's exact test was used for statistics. Results: The most frequent PIK3CA mutations were found in the kinase domain (KD) in both endometrial and breast cancers (predominately p.H1047). In lung and colorectal cancers, helical domain alterations were predominant. There were significantly more PIK3CA adaptor binding domain mutations and PIK3CA/PTEN co-mutations in endometrial cancer compared to other tumor types. Among PIK3CA/PTEN co-mutations in endometrial cancer, there were significantly fewer TP53 mutations when compared to those with no PTEN co-mutation (17.2% vs. 70.7%; p&amp;lt;0.0001). Conclusions: In endometrial cancer, PTEN is more frequently mutated upon PI3K/AKT pathway hyperactivation, abrogating its normal inhibitory effect on PI3K resulting in increased cell proliferation and survival. When PTEN is not mutated, alternations downstream of AKT, such as TP53 mutations, may serve as alternative cell survival regulators. This may account for the relationship between PTEN/PIK3CA KD co-mutation and TP53 mutation. While PIK3CA KD mutations are similarly predominant in breast and endometrial cancer, the PTEN feedback loop is disrupted in endometrial cancer. This study provides insight into the patterns of molecular alterations present within PIK3CA-mutated patients, which could be instrumental in stratifying patient populations. PIK3CA Mutation Prevalence Adapter binding domain Helical domain Kinase domain Hotspot H1047 PTEN co-mutation + any PIK3CA mutation Endometrial (n=99) 21.2% 26.3% 42.4% 27.3% 58.6% Breast (n=278 ) 3.6% (p&amp;lt;0.0001) 37.8% (p=0.0386) 55.4% (p=0.0258) 46.8% (p=0.0007) 7.2% (p&amp;lt;0.0001) Lung (n=452) 8.8% (p=0.0004) 50.2% (p&amp;lt;0.0001) 24.6% (p=0.0003) 8.4% (p&amp;lt;0.0001) 5.5% (p&amp;lt;0.0001) Colorectal (n=342) 9.9% (p=0.0027) 51.5% (p&amp;lt;0.0001) 25.1% (p=0.0008) 16.4% (p=0.0147) 8.2% (p&amp;lt;0.0001) Citation Format: Madhuri Paul, Frank J. Scarpa, Rachel Daringer, Sally Agersborg, Vincent Anthony Funari, Forrest Blocker. Pattern of PIK3CA co-alterations in endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2934.
Abstract 3739: EM-seq permits accurate and precise methylome analysis of cfDNA and FFPE DNA
Authors: Louise Williams
Journal: Cancer Research (2022)

Abstract The study of DNA methylation from cell-free DNA (cfDNA) and DNA extracted from formalin fixed paraffin embedded (FFPE) tissues are notoriously difficult. The use of these DNA inputs is becoming increasingly important in the field of cancer diagnostics. The cytosine modifications, 5-methylcytosines (5mC) and 5-hydroxymethylcytosines (5hmC), are key epigenetic factors that play an important role in cellular processes and their mis-regulation results in diseased states like cancer. Advances in the study of these epigenetic factors in combination with improvements in sample preparation have enabled cancer biomarker identification based on methylation profiling. The historical gold standard for detecting cytosine methylation has been bisulfite sequencing. This method uses chemical conversion of cytosines into uracils and has been used for both targeted and whole genome methylation analysis. However, bisulfite conversion leads to DNA damage which results in shorter DNA insert sizes as well as biases in the data. It is challenging to make bisulfite libraries from cfDNA and FFPE DNA as typically the DNA is of low quantity and quality. We developed an enzyme-based methylation detection technology (EM-seq) to address the flaws inherent to bisulfite sequencing. This method, primarily due to the intact nature of DNA after conversion, results in better quality libraries with longer insert sizes, lower duplication rates and minimal GC bias. EM-seq libraries prepared from cfDNA and lung FFPE DNA had longer inserts, lower duplication rates, higher percentages of mapped reads and less GC bias compared to bisulfite libraries. EM-seq libraries also identified a higher number of CpGs with even coverage facilitating accurate methylation calling. EM-seq’s superior sequencing metrics establish it as a standard method for robust methylation profiling, particularly for these types of challenging DNA samples. Citation Format: Louise Williams. EM-seq permits accurate and precise methylome analysis of cfDNA and FFPE DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3739.
Abstract LB530: A potent and selective small molecule antagonist of PD-L1 ABSK043 demonstrates significant anti-tumor efficacy in combination with other agents in preclinical models
Authors: Haiyan Ying, Yongxian Zhang, Fei Yang, Wenqun Xin, Jiaqi Song, Zhui Chen
Journal: Cancer Research (2022)

Abstract Immunotherapy has revolutionized cancer treatment in the last decade. Several monoclonal PD-1 and PD-L1 antibodies have been approved for various cancers. Unlike antibodies, small molecule inhibitors may offer potential advantages in oral dosing, adjustable control of drug exposure, improved tumor penetration and many other aspects. Therefore, small molecule antagonist which can efficiently abolish interaction of PD-1 and PD-L1 may render a novel alternative treatment approach with potentially improved clinical benefits. ABSK043, an oral small molecule inhibitor of PD-L1 discovered by us, has entered into clinical Phase I in 2021. Preclinically, ABSK043 has shown significant tumor growth inhibition as a single agent in multiple models. To explore potential synergy of ABSK043 with other therapeutic agents, in vivo combination experiments were conducted. In this work, we present in vivo combination results for ABSK043 with several therapeutic agents such as a VEGFR inhibitor axitinib, or carboplatin, a key component of the widely used CRC standard-of care chemotherapy treatment regimen, as well as other immune-oncology agents. These combinations demonstrated strong in vivo synergy in tumor mouse syngeneic models. Taken together, these data for the first time demonstrated combination synergy of a small molecule PD-L1 inhibitor with other agents and pave the road for potential clinical evaluation of combination treatment of ABSK043 with these agents in patients. Citation Format: Haiyan Ying, Yongxian Zhang, Fei Yang, Wenqun Xin, Jiaqi Song, Zhui Chen. A potent and selective small molecule antagonist of PD-L1 ABSK043 demonstrates significant anti-tumor efficacy in combination with other agents in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB530.